Antitumor agents--CLXXV. Anti-tubulin action of (+)-thiocolchicine prepared by partial synthesis.
(+)-Thiocolchicine (2b) was prepared from (+/-)-colchicine (1) in a five-step reaction sequence that included chromatographic separation of appropriate camphanylated diastereomers. Acid hydrolysis of the (+)-diastereomer, followed by acetylation, yielded the desired product 2b. (+)-Thiocolchicine has 15-fold lower inhibitory activity against tubulin polymerization than (-)-thiocolchicine, and is 29-fold less potent for inhibiting growth of human Burkitt lymphoma cells. The enantiomer 2a, prepared from the (-)-camphanylated diastereomer, had potent activity in all assays comparable to that of (-)-thiocolchicine prepared by other methods. These results support the hypothesis that the proper configuration of colchicine-related compounds is an important requirement for their anti-tubulin action.
Shi
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Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill 27599, USA.
Verdier-Pinard
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Brossi
A
A
Hamel
E
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Lee
K H
KH
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D003078:Colchicine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D050257:Tubulin Modulators; C014856:thiocholchicine; D003078:Colchicine